GI Physiology Module: Absorption of Water and Ions

1. GI Physiology Module:Absorption of Water and Ions Jason Soden MD University of Colorado School of Medicine Children’s Hospital Colorado Reviewers: George Fuchs MD: UAMS College of Medicine / Arkansas Children’s Hospital Wayne Lencer MD: Harvard Medical School / Boston Children’s Hospital

2. NASPGHAN Physiology Education Series Series Editors: Christine Waasdorp Hurtado, MD, MSCS, FAAP Christine.Waasdorp@childrenscolorado.org Daniel Kamin, MD Daniel.Kamin@childrens.harvard.edu

3. Objectives • Understand the mechanisms of intestinal transport of ions • Know the location of transport and secretion of ions • Understand the absorption of vitamins and minerals • Understand the phenomenon of changes in nutrient absorption with luminal nutrient concentration • Mechanisms of diarrhea • Identify signs and symptoms of excess vitamin and mineral absorption and signs and symptoms of deficiency

4. Key Concepts: GI Fluid and Electrolyte Balance • Regulation of fluid transport in the gut is critical for normal intestinal function • Large amounts of fluid are secreted into and absorbed from the gut daily • Because water follows an osmotic gradient, the understanding of electrolyte transit is key to understanding intestinal fluid balance in health and disease

5. Intestinal Epithelial Cells as Gatekeepers for Ion and Fluid Movement secretion APICAL mucous layer mucous layer BASOLATERAL absorption

6. Tight Junctions secretion APICAL Intracellular TIGHT JUNCTIONS restrict passive flow of solutes after secretion or absorption mucous layer mucous layer BASOLATERAL absorption

7. Transepithelial Transport: Transcellular • Employs membrane transporters to move molecules and water through cells • May work against electrochemical gradient • Requires energy/ATP • Subject to transcriptional and posttranscriptional regulation secretion APICAL mucous layer mucous layer BASOLATERAL absorption

8. Mechanisms of Transcellular Transport

9. Transepithelial Transport: Paracellular secretion • Movement of solutes and water through tight junctions • Dictated primarily by electrochemical gradient APICAL mucous layer mucous layer BASOLATERAL absorption

10. Transepithelial Transport: Summary MEMBRANE TRANSPORT PROTEINS drive TRANSCELLULAR transport of ions, which sets up ELECTROCHEMICAL GRADIENT to allow PARACELLULAR transport of fluid through TIGHT JUNCTIONS mucous layer mucous layer Transcellular Paracellular Sets up electrochemical gradients

11. Water Transport Solute Transport Overview of fluid movement in the GI tract

12. Overview of fluid movement in the GI tract NET Fluid entering bowel: 8.5 L / day NET Fluid reabsorbed by bowel: 8.4 L / day NET Fluid loss via stool: 100 mL / day

13. Anatomic Considerations • Based on the functional structure of the villi and crypts, simultaneous secretion and absorption occur at all levels of the intestine • Based on surface amplification of the intestine, surface area (and function) increase by 600 FOLD • The small intestine and colon have separate functions, primarily related to expression and localization of epithelial transport systems

14. Gut Surface Area Amplification http://www.cartoonstock.com/newscartoons/cartoonists/dcl/lowres/dcln57l.jpg http://flylib.com/books/en/2.953.1.30/1/ http://www.daviddarling.info/encyclopedia/S/small_intestine.html

15. Location – Based Specialization within the Gut Proximal Small Intestine Colon Tight Junctions more permeable Tight Junctions less permeable Absorption: Nutrients Vitamins Minerals Salt and Water Absorption: Sodium Water

16. Simultaneous secretion and absorption occur in any segment of the intestine • Villi = Absorption • Fluid absorption primarily depends on sodium transport • Na may be Coupled with chloride, nutrients, bile acids, and other solutes • Crypt = Secretion • Primarily follows Chloride and bicarbonate

17. Small Intestinal Ion Transport Mechanisms • Ion transport: • Bicarbonate secretion • Electroneutral NaCl absorption • Chloride Secretion • Nutrient, mineral, other: • Sodium-coupled nutrient absorption • Proton-coupled nutrient absorption • Sodium-coupled bile acid absorption • Calcium absorption • Iron absorption

18. Colonic ion transport mechanisms • Sodium Absorption: • Electrogenic sodium absorption • Electroneutral NaCl Absorption • Potassium secretion and absorption • Chloride secretion • Short Chain fatty acid (SCFA)absorption

19. Cellular Basis of Transport • Summarize key examples of transport proteins • Examples: • Sodium • Chloride • bicarbonate • Describe mechanisms of diarrhea

20. Concept 1: Na, K ATPase Lumen Na, K ATPase creates a Na electrochemical gradient between enterocyte and lumen Na+ K+ Basolateral Apical Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

21. Concept 2: Na Coupled Transport Lumen The Na gradient created by Na, K ATPase allows Na-coupled transport from lumen into cell Glucose Na+ Na+ AA Na+ H+ K+ Na+ Basolateral Apical Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

22. Clinical Application: Oral Rehydration Solution O.R.S. Lumen Glucose Na+ Na+ Na+ H+ K+ Na+ Basolateral Apical Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

23. Concept 3: NaCl Co-transport is mediated by TWO transport proteins Lumen Na/H (cation) exchanger works in conjunction with HCO3/Cl (anion) exchanger, allowing NaCl absorption Na+ Na+ H+ K+ Cl - HCO3- Basolateral Apical Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

24. Concept 4: Chloride secretion occurs in conjunction with basolateral Na, K, Cl transport Lumen Na+ K+ Cl (2) -- Na+ K+ Cl (2) -- Cl - Na-K ATPase drives Na gradient, further allowing Cl secretion through apical CFTR channel Na+ CFTR chloride channel K+ Basolateral Apical Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

25. Concept 5: Water follows NaCl Lumen WATER Water will travel through intercellular tight junctions in the setting of NaCl absorption Na+ Na+ H+ K+ Cl - HCO3- Basolateral Apical Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

26. Absorption and Secretion in Health versus Diarrheal States NaCl, Nutrient absorption NaCl absorption Chloride secretion Chloride Secretion Diarrhea Healthy Adapted from: Barrett KE: Gastrointestinal Physiology. www.accessmedicine.com

27. Multiple Systems Interact in Regulation of Ion Transport and Secretion

28. Multiple Systems Interact in Regulation of Ion Transport and Secretion • Key to Pathophysiology: • Infection, inflammation, gut hormones, and ENS chemical mediators all regulate transport mechanisms • Repetitive or redundant pathways, including cAMP, cGMP, and Calcium activation

29. Mechanisms of Diarrhea: Osmotic versus Secretory Small Intestine Colon Secretory Diarrhea: Crypt secretion leads to more prominent small intestinal losses Osmotic Diarrhea: Solute-driven water losses more prominent in the colon Adapted from: Guandalini “Acute Diarrhea” Pediatric Gastrointestinal Disease. 4th Ed 2004

30. Mechanisms of Bacterial Pathogens Adapted from: Fasano: “Bacterial Infections” Pediatric Gastrointestinal Disease. 4th Ed 2004

31. cAMP and Chloride secretion Adapted from: Barrett KE: Gastrointestinal Physiology. www.accessmedicine.com

32. Pathogenesis of Cholera 3. Increase in Chloride secretion via CFTR channel 2. Increase in cAMP 1. Cholera Toxin activates Gs Protein Adapted from: Barrett KE: Gastrointestinal Physiology. www.accessmedicine.com

33. CFTR mutation and cholera Adapted from: Barrett KE: Gastrointestinal Physiology. www.accessmedicine.com

34. Minerals and Vitamins • Iron • Calcium • Magnesium • Water Soluble Vitamins • Fat Soluble Vitamins

35. Iron Metabolism and Balance ~3500mg total in body ~ 2000mg Most ingested iron ends up in stool in health Adapted from Modern Nutrition, 10th Ed

36. Iron Absorption H+

37. Calcium and Magnesium Absorption • Calcium • Absorbed primarily in duodenum • 1,25 OH Vit D regulates: • Enterocyte apical Ca Channel • Intracellular protein calbindin (shepards to export pump) • Basolateral Ca-ATPase • Vit D independent transport follows concentration gradient • Magnesium • Absorbed throughout GI tract • Regulation of Mg absorption is dependent on dietary intake • Mg Channel upregulated in low Mg states to promote absorption

38. Water Soluble Vitamins • Vitamin C • B vitamins • Thiamine • Riboflavin • Niacin • B6 • Folate • B12 • Biotin • Pantothenic acid • Water soluble • Taken up easily by cells (B12 requires IF) • In general, water soluble vitamins are not stored in tissue • Exclusions: B12 (liver storage)

39. Fat Soluble Vitamins • A • D • E • K • Digested, absorbed, and transported with dietary fat • Stored in liver, fat cells

40. Soden: Seminars in Ped Surgery 2010

41. Summary • Electrolyte absorption and secretion is tightly regulated, and forms the basis of fluid and solute transport and balance in both healthy and diarrheal states • Individual mechanisms exist for mineral and vitamin absorption and transport

42. Please send any questions or comments to •Christine.Waasdorp@childrenscolorado.org •Daniel.Kamin@childrens.harvard.edu